Breathing is a highly regulated process that requires precise coordination among the muscles that cause ventilation and those responsible for maintenance of upper airway patency. Failure to properly activate the upper airway dilator muscles in response to an increase in inspiratory drive can result in obstruction of the upper airways. High fidelity synaptic signaling across the neuromuscular junction is required for precise regulation of upper airway patency that corresponds to the level of inspiratory drive. The major synaptic component of the neuromuscular junction is the nicotinic acetylcholine receptor (nAChR), a ligand (ACh)- gated channel that is composed of four homologous trans-membrane subunits (alpha2, beta, epsilon, gamma) arranged in a pentamer. During early postnatal development the nAChR undergoes a structural modification which impacts on its ability to respond to ACh released from motoneurons. In the neonate, the nAChR contains a gamma- instead of the epsilon-subunit. The nAChR-gamma exhibits a lower single channel conductance than the adult nAChR-epsilon. Thus, muscles that express more nACh-gamma and less nAChR-epsilon might be prone to hypotonicity and less responsive to synaptic input. We hypothesize that discordant regulation of the nAChR-gamma and nAChR-epsilon isoforms could lead to reduced upper airway patency and airway obstruction There is growing evidence that opposing kinase and phosphatase pathways in muscle regulate the nAChR-gamma to nAChR-epsilon transition during early postnatal development. Moreover, recent findings indicate that both the kinase and phosphatase activities are regulated by "trophic" factors released from the motoneurons. The proposed research will investigate the role of the tetradecapeptide somatostatin (SST) in the regulation of tyrosyl phosphatase (PTPase) activities in muscle. Preliminary results show that SST, which is expressed developmentally in the motoneurons that innervate the upper airways, prevents induction of -subunit gene expression by the kinase pathway. The specific aims are: 1) Identify and characterize the protein tyrosyl phosphatases that are activated by SST and cause inhibition of epsilon-subunit gene expression; 2) Determine the mechanism by which SST-induced PTPases oppose kinase pathways to prevent activation of epsilon-subunit gene expression; and 3) Determine the effect of continuous expression of the SST-SSTR-PTPase pathway on epsilon-subunit gene expression in genetically engineered mice.